1. Technical Field
The present invention relates to a pharmaceutical composition for inhibiting angiogenesis, the composition containing, as an effective ingredient, a novel synthetic low-molecular compound targeting ubiquinol-cytochrome c reductase binding protein (UQCRB).
2. Description of the Related Art
Angiogenesis is a key process for progression of many solid tumors. Accordingly, the efficient inhibition of angiogenesis is considered to be a powerful way to suppress tumor growth and metastasis. Consequently, several specific target proteins of angiogenesis, including vascular endothelial growth factor receptors (VEGFs), matrix metalloproteinases, aminopeptidases, histone deacetylases, and calmodulin, have been identified and anti-angiogenic agents of various scaffolds have been developed based on their inhibitory activities toward the specific targets. We recently isolated terpestacin, a new angiogenesis inhibitor with a unique bicyclo sesterterpene structure, from fungal metabolites. To investigate the molecular mechanism of terpestacin regarding its anti-angiogenic activity, we identified a cellular binding protein of terpestacin using a reverse chemical proteomics approach. Terpestacin specifically bound to the 13.4-kDa subunit (UQCRB) of complex III in the mitochondrial respiratory chain. Recent reports have suggested that reactive oxygen species (ROS) generation at mitochondrial complex III triggers hypoxia-inducible factor-1a (HIF-1a) stabilization during hypoxia. Indeed, terpestacin binding to UQCRB inhibited hypoxia-induced ROS generation, leading to inhibition of HIF-1a and tumor angiogenesis in vivo, without disrupting mitochondrial respiration and complex III functional structure. In addition, the regulation of UQCRB expression demonstrated that the protein is a critical mediator of hypoxia-induced tumor angiogenesis via mitochondrial ROS-mediated signaling. This discovery suggested that small molecules targeting UQCRB in mitochondrial complex III can suppress tumor angiogenesis without acting as a respiratory poison. As such, we attempted to develop new small molecules that specifically regulate the function of UQCRB.
Throughout the specification, a number of publications and patent documents are referred to and cited. The disclosure of the cited publications and patent documents is incorporated herein by reference in its entirety to more clearly describe the state of the related art and the present disclosure.